Drs. Lea Starita (left) and Clare Turnbull:
'Key barriers to clinical adoption of functional data remain, including uncertainty in how to use the data, data availability for clinical use, and a lack of time to assess functional data being reported, factors in non-use of functional data.'
A working group of the Atlas of Variant Effects (AVE) Alliance has undertaken a task as much-needed as it is long and overdue: developing more definitive guidelines for genetic variant classification.
The group, the ClinGen/AVE Functional Data Working Group, has more than 25 international members from academia, government, and the private sector. It is co-chaired by BBI’s Lea Starita, Ph.D. and Professor Clare Turnbull, M.D., Ph.D., of the Institute of Cancer Research in London.
“The original guidelines for using functional data were an excellent start, but it turns out that a few instructions were a bit vague,” said Starita. “Therefore, people have been interpreting rules differently, depending on where they are coming from and their use case. So, we’re hoping to promote more standardized usage.”
Turnbull outlined what she believes are three key objectives of the group:
- Developing clear, robust guidelines that are acceptable to and useable by our clinical diagnostic scientists and clinicians.
- Fostering foster partnerships with expert groups, such as Variant Curation Expert Panels, and finding ways of co-working that enable utilization for variant classification of functional data, especially multiplexed assays of variant effect (MAVEs) for their respective genes.
- Providing educational outreach to ensure MAVE data is accessible and usable for clinical uptake.
That “clinical uptake” is essential, said Turnbull.
“Key barriers to clinical adoption of functional data remain, including uncertainty in how to use the data, data availability for clinical use, and a lack of time to assess functional data being reported, factors in non-use of functional data,” she said. “Our working group is seeking to address these barriers to empower the use of new functional data in a clinical setting.”
The working group’s efforts are guided by two important documents.
The first is a report on a workshop, “The clinical application of data from multiplex assays of variant effect (MAVEs),” that Starita, Turnbull and others presented in July of 2023 at the Wellcome Genome Campus in the UK.:
“The workshop articulated the urgent requirement for more systematic clinical validation of assay data,” the report states. “However, clear solutions were lacking for how this clinical validation service might feasibly be delivered as data curation efforts are labor intensive and difficult to fund through many grant mechanisms…. there was widespread consensus regarding the need for more flexible approaches to assay validation, such as aggregating sets of rare missense variants with similar assay results to validate which assay outcomes correspond best with clinical case-control data, and more flexible approaches to the systematic generation of benign truth-sets.”
The other document is a pre-print paper, “Combining multiplexed functional data to improve variant classification” from last March that states:
“The high likelihood that a newly observed variant will be a VUS has made interpretation of genetic variants a substantial bottleneck in clinical genetics…. Furthermore, variants identified in individuals of non-European-like genetic ancestries are often confounded by the limited diversity of our population databases, causing substantial inequity in diagnosis and treatment… The last decade has seen an explosion of MAVEs measuring millions of variant effects that use different modalities to study variants in a variety of clinically important genes…. The next decade is likely to see an increasing number of genes for which two or more multiplex functional datasets are available.”
In addition to Starita and Turnbull, two other members of the ClinGen/AVE Functional Data Working Group expressed their hopes for the group’s work.
Rehan Villani, Ph.D., a Research Officer with the Australia-based QIMR Berghofer Medical Research Group, noted three top objectives:
- Improved and increased identification of the underlying cause of disease for more patients.
- Worldwide improvement of practice for genomic diagnostic testing.
- Building international networks and collaborations that will decrease the time for translating research into clinical benefit.
“Through this group, the work we do at QIMR Berghofer developing diagnostic genomics methods is used to inform real world expert recommendations that can be actioned internationally,” Villani said. “The outcomes of the FWG ensure that the work we do at QIMR Berghofer has impact on real patients, worldwide.”
In addition, Tina Pesaran, M.A., M.S., Vice President for Genomic Science with Ambry Genetics, anticipates the working group will provide high-level guidance, particularly for integrating MAVE data into variant classification that is aligned with recommendations of the American College of Medical Genetics and Genomics.
“I hope that we can address key issues that plague Variant Curation Expert Panels and clinical variant curation communities, including defining truth sets, setting thresholds, and clarifying how to combine data from multiple assays,” Pesaran said. “Crucially, it will be important to consider how MAVE-derived evidence fits alongside other types of evidence codes, especially in silico predictions, to ensure coherent and balanced variant interpretation frameworks.”
Some might contend that the size of the working group – 29 individuals from 24 organizations – would hinder progress toward achieving its objectives.
Starita disagrees.
“There is a compelling need for a unified voice across ClinGen’s efforts and beyond that, people from industry, to ‘kick the tires’ and test what we’re doing,” she said. “Being able to work with all those people in the same room is amazing.”
